Strontium titanium trioxide

Endpoint summary

Description of key information

Two studies have been carried out to assess the potential for irritation of the test material in eyes and skin.
Both studies concluded that the test material can be considered to be non-irritating to eyes and skin.

Key value for chemical safety assessment

Skin irritation / corrosion

Link to relevant study records

Reference

Endpoint:

skin irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

09 May 2002 and 22 May 2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficincies, which do not affect the quality of relevant results.

Qualifier:

according to guideline

Guideline:

EU Method B.4 (Acute Toxicity: Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

Please see "Principles of method" for details.

Qualifier:

according to guideline

Guideline:

OECD Guideline 404 (Acute Dermal Irritation / Corrosion)

Deviations:

yes

Remarks:

Please see "Principles of method" for details.

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2500 (Acute Dermal Irritation)

Deviations:

yes

Remarks:

Please see "Principles of method" for details.

Principles of method if other than guideline:

The Study Protocol indicated that a suitably sized area of skin (dorso-Iumbar region) should be clipped free of hair on the day before administration, however, on the subject study two animals (numbers 33960 and 3962) were clipped two days before administration. Since the test and control sites of each animal were examined immediately prior to treatment and were found to be satisfactory, it is considered that this protocol deviation has had no impact on the study outcome.

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or test system and environmental conditions:

Animals for this study were selected from a stock supply of healthy adult rabbits of the New Zealand White strain, obtained from Highgate Farm, Market Rasen, Lincolnshire, England.
They were in the weight range of 3.44 to 3.60 kg and at least eight weeks of age, prior to treatment (Day 1). All rabbits were acclimatised to the experimental environment for a period of at least 18 days prior to the start of the study.
The rabbits were selected without conscious bias for the study. They were housed individually in stainless steel cages with perforated floors at the Eye Research Centre, Eye, Suffolk, IP23 7PX.
A standard laboratory rabbit diet (Special Diet Services STANRAB (P) SQC pellet) and drinking water were provided ad libitum. The batch of diet used for the study was analysed by the supplier for nutrients, possible contaminants and micro-organisms likely to be present in the diet and which, if in excess of specified amounts, might have an undesirable effect on the test system. The animals were given a dietary supplement of hay.
During the acclimatisation and study period the animals were given small soft white untreated wood blocks for environmental enrichment.
Results of routine physical and chemical examination of drinking water, as conducted by the supplier are made available to Huntingdon Life Sciences Limited.
Animal room environmental controls were set to maintain temperature within the range 15 to 23°C, and relative humidity within 40 to 70%. These environmental parameters were recorded and the permanent record archived with other departmental raw data. Lighting was controlled by means of a time switch to give 12 hours of artificial light (06:00 to 18:00 GMT) in each 24 hour period.
Each animal was identified by a numbered tag placed through the edge of one ear. This identification was unique within the Department throughout the duration of the study. Each cage was identified by a coloured label displaying the study number, animal number, phase of study and initials of the Study Director and Home Office licensee.

Type of coverage:

semiocclusive

Preparation of test site:

clipped

Vehicle:

unchanged (no vehicle)

Controls:

other: An additional skin site was similarly treated with the exception of test substance and acted as a control.

Amount / concentration applied:

TEST MATERIAL
The treatment site was 'wetted' with 0.5mL of reverse osmosis water and approximately 0.5 g of the test substance was applied under a 2-ply 25 mm x 25 mm porous gauze pad to intact skin sites

Duration of treatment / exposure:

4 hours

Observation period:

72 hours

Number of animals:

Three

Details on study design:

TEST SITE
On the day before application of the test substance, hair was removed with clippers from the dorso-lumbar region of each rabbit exposing an appropriate sized area of skin.
The treatment site was 'wetted' with 0.5mL of reverse osmosis water and approximately 0.5 g of the test substance was applied under a 2-ply 25 mm x 25 mm porous gauze pad to intact skin sites on three animals. An additional site was similarly treated with the exception of test substance and acted as a control.
A single animal received three exposures (of three minutes, one or four hours duration) in a step-wise manner and acted as a preliminary screen. In the absence of a severe effect on removal of the dressings the next exposure was initiated.
For exposures of one hour or more each treatment site was covered with "Tubigrip" elasticated bandage dressing for the duration of the exposure period. The animals were returned to their cages immediately after treatment.

REMOVAL OF TEST SUBSTANCE
At the end of the exposure period the semi-occlusive dressing and gauze pad were removed and the treatment site was washed with luke warm water (30-40°C) to remove any residual test substance. The treated area was blotted dry with absorbent paper.

OBSERVATIONS
Clinical signs
All animals were observed daily for signs of ill health or toxicity.
Dermal responses
Examination of the treated skin was made on removal of the dressings (for 3 minute or one hour exposures) and approximately 1, 24, 48 and 72 hours later. Only the data for the four hour exposure are reported, the data from the three minute and one hour exposures are held in the archives.

SCORING SYSTEM:
Local dermal irritation was assessed using the prescribed numerical system detailed in "any other information on materials and methods" below.

Irritation parameter:

erythema score

Basis:

animal #1

Remarks:

3945 (male)

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: No effects noted.

Irritation parameter:

erythema score

Basis:

animal #2

Remarks:

3960 (male)

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: No effects noted.

Irritation parameter:

erythema score

Basis:

animal #3

Remarks:

3962 (male)

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: No effects noted.

Irritation parameter:

edema score

Basis:

animal #1

Remarks:

3945 (male)

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: No effects noted.

Irritation parameter:

edema score

Basis:

animal #2

Remarks:

3960 (male)

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: No effects noted.

Irritation parameter:

edema score

Basis:

animal #3

Remarks:

3962 (male)

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: No effects noted.

Irritant / corrosive response data:

No dermal irritation was observed in any animal throughout the duration ofthe study.

Other effects:

CLINICAL SIGNS
There was no sign of toxicity or ill health in any rabbit during the observation period.

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The Primary Irritation Index (PII) was calculated to be 0.0 and ST888YK was classified as "non irritant" in accordance with the criteria of ECETOC.
The test material is not considered to be classified as irritating to skin according to Regulation (EC) No 1272/2008.

Executive summary:

A study was performed to assess the skin irritation potential of ST888YK to the rabbit. The method followed was that described in:

EEC Methods for the determination of toxicity, Annex to Directive 92/69/EEC (Official Journal No. L383A, 29.12.92), Part B, Method B.4. Acute toxicity (Skin Irritation).

OECD Guideline for Testing of Chemicals No. 404 "Acute Dermal Irritation/Corrosion". Adopted 17 July 1992.

EPA Health Effects Test Guidelines OPPTS 870.2500 Acute Dermal Irritation EPA 712-C-98196. August 1998.

Three rabbits received a single four hour, semi-occlusive, dermal administration of approximately 0.5 g of the test substance as supplied and were observed for four days.

No dermal irritation was observed in any animal throughout the duration of the study.

The means of scores for these reactions at approximately 24, 48 and 72 hours after administration, calculated separately for each animal, are summarised below:

Means of scores at approximately 24, 48 and 72 hours
Animal number	Erythema	Oedema
3945	0.0	0.0
3960	0.0	0.0
3962	0.0	0.0
EC trigger values*	≥ 2	≥ 2

*Classification is triggered if means of scores for either effect are ≥ 2 for two or three animals (or if effects persist to Day 14 in at least two animals).

The Primary Irritation Index (PII) was calculated to be 0.0 and ST888YK was classified as "non irritant" in accordance with the criteria of ECETOC.

The test material is not considered to be classified as irritating to skin according to Regulation (EC) No 1272/2008.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Eye irritation

Link to relevant study records

Reference

Endpoint:

eye irritation: in vivo

Type of information:

experimental study

Adequacy of study:

key study

Study period:

22 May 2002 and 07 June 2002

Reliability:

1 (reliable without restriction)

Rationale for reliability incl. deficiencies:

other: Study conducted in compliance with agreed protocols, with no or minor deviations from standard test guidelines and/or minor methodological deficincies, which do not affect the quality of relevant results.

Qualifier:

according to guideline

Guideline:

EU Method B.5 (Acute Toxicity: Eye Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

OECD Guideline 405 (Acute Eye Irritation / Corrosion)

Deviations:

no

Qualifier:

according to guideline

Guideline:

EPA OPPTS 870.2400 (Acute Eye Irritation)

Deviations:

no

GLP compliance:

yes (incl. QA statement)

Species:

rabbit

Strain:

New Zealand White

Details on test animals or tissues and environmental conditions:

Animals for this study were selected from a stock supply of healthy adult rabbits of the New Zealand White strain, obtained from Highgate Farm, Market Rasen, Lincolnshire, England.
They were in the weight range of 3.00 to 3.67 kg and at least eight weeks of age, prior to treatment (Day 1). All rabbits were acclimatised to the experimental environment for a period of at least five days prior to the start ofthe study.
The rabbits were selected without conscious bias for the study. They were housed individually in stainless steel cages with perforated floors at the Eye Research Centre, Eye, Suffolk, IP23 7PX.
A standard laboratory rabbit diet (Special Diet Services STANRAB (P) SQC pellet) and drinking water were provided ad libitum. The batch of diet used for the study was analysed by the supplier for nutrients, possible contaminants and micro-organisms likely to be present in the diet and which, if in excess of specified amounts, might have an undesirable effect on the test system. A dietary supplement of hay was given.
During the acclimatisation and study period the animals were given small soft white untreated wood blocks for environmental enrichment.
Results of routine physical and chemical examination of drinking water, as conducted by the supplier are made available to Huntingdon Life Sciences Limited.
Animal room environmental controls were set to maintain temperature within the range 15 to 23°C, and relative humidity within 40 to 70%. These environmental parameters were recorded and the permanent record archived with other departmental raw data. Lighting was controlled by means of a time switch to give 12 hours of artificial light (06:00 to 18:00 GMT) in each 24 hour period.
Each animal was identified by a numbered tag placed through the edge of one ear. This identification was unique within the Department throughout the duration of the study. Each cage was identified by a coloured label displaying the study number, animal number, phase of study and initials of the Study Director and Home Office licensee.

Vehicle:

unchanged (no vehicle)

Controls:

other: The untreated eye was used as a comparison with the treated eye during assessment of ocular lesions.

Amount / concentration applied:

TEST MATERIAL
ST888YK was administered as supplied by the Sponsor.
The absorption of ST888YK was not determined.
The specific gravity of the test substance was approximated and the weight of ST888YK that occupied 0.1 mL was determined. Aliquots of this weight were prepared.

Duration of treatment / exposure:

The dose was instilled into the right eye by pulling the lower eyelid away from the eye ball to form a cup into which the test substance was dropped. The eyelids were then gently held together for one second.

Observation period (in vivo):

0, 1, 24, 48 and 72 hours; 7 days

Number of animals or in vitro replicates:

Three.

Details on study design:

The eyes of each animal were examined prior to instillation of the test substance to ensure that there was no pre-existing corneal damage, iridial inflammation or conjunctival irritation. Each animal was gently restrained.

OBSERVATIONS
Clinical signs
The behaviour of each rabbit was observed immediately following instillation of the test substance to allow assessment of the initial pain response by the criteria detailed in "any other information on materials and methods" below.
The animals were returned to their cages and checked at least twice during the first hour after dosing and at regular intervals throughout the day to ensure no severe injury passed unnoticed. Ocular reactions to treatment were assessed 1, 24, 48 and 72 hours and 7 days after treatment, according to the criteria
detailed in "any other information on materials and methods" below. Reactions not included below were described in detail.

An ophthalmoscope or pencil beam torch was used to facilitate inspection ofthe eyes.

Interpretation of results
The classification system of Kay and Calandra (1962)* was employed on this study. This system classifies ocular irritants thus:

Corneal scoring using the grade for degree of opacity density (A) and the grade for the area of cornea involved (B):

Corneal score =A x B x 5 (theoretical maximum = 80)

Iridial scoring using the grades for iritis (C):

Iridial score = C x 5 (theoretical maximum = 10)

Conjunctival score using the grade for conjunctival redness (D), chemosis grade (E) and grade for discharge (F):

Conjunctival score =(D + E + F) x2 (theoretical maximum =20)

The scores for each area are meaned for each time point and the highest total meaned score is used for the classification thus:

Total mean score Classification
0.0-0.5 Non-irritating
0.5 -2.5 Practically non-irritating
2.5 - 15 Minimally irritating
15 -25 Mildly irritating
25 -50 Moderately irritating
50-80 Severely irritating
80-100 Extremely irritating
100 - 110 Maximally irritating

* Kay, JH & Calandra, JC (1962) Interpretation of Eye Irritation Tests. Journal of the Society of Cosmetic Chemists.

Assessment of pain response on instillation
The observed pain response following instillation of the test substance was reported separately.
Mortality and termination procedure
The animals were killed after completion ofthe observation periods.

Irritation parameter:

cornea opacity score

Basis:

animal #1

Remarks:

3984 (male)

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: No effects noted.

Irritation parameter:

cornea opacity score

Basis:

animal #2

Remarks:

4117 (male)

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: No effects noted.

Irritation parameter:

cornea opacity score

Basis:

animal #3

Remarks:

4118 (male)

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: No effects noted.

Irritation parameter:

iris score

Basis:

animal #1

Remarks:

3984 (male)

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

3

Reversibility:

other: No effects noted.

Irritation parameter:

iris score

Basis:

animal #2

Remarks:

4117 (male)

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

3

Reversibility:

other: No effects noted.

Irritation parameter:

iris score

Basis:

animal #3

Remarks:

4118 (male)

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

3

Reversibility:

other: No effects noted.

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #1

Remarks:

3984 (male)

Time point:

other: Mean of 24, 48 and 72 hours

Score:

1

Max. score:

3

Reversibility:

fully reversible within: 7 days

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #2

Remarks:

4117 (male)

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0.33

Max. score:

3

Reversibility:

fully reversible within: 48 hours

Irritation parameter:

conjunctivae score

Remarks:

redness

Basis:

animal #3

Remarks:

4118 (male)

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0.66

Max. score:

3

Reversibility:

fully reversible within: 72 hours

Irritation parameter:

chemosis score

Basis:

animal #1

Remarks:

3984 (male)

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: No effects noted.

Irritation parameter:

chemosis score

Basis:

animal #2

Remarks:

4117 (male)

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: No effects noted.

Irritation parameter:

chemosis score

Basis:

animal #3

Remarks:

4118 (male)

Time point:

other: Mean of 24, 48 and 72 hours

Score:

0

Max. score:

4

Reversibility:

other: No effects noted.

Irritant / corrosive response data:

OCULAR REACTIONS
Injection of the conjunctival blood vessels with or without very-slight or slight discharge was apparent during the first twenty-four hours after instillation. The injection was apparent in two animals at the 48-hour assessment and in one animal 24 hours later. No other ocular reaction was apparent in any animal at any time.
Instillation of the test substance gave rise to a moderate initial pain response in one animal; no pain response was evident in the other two animals.

Other effects:

CLINICAL SIGNS
There was no sign of toxicity or ill health in any rabbit during the observation period.

Interpretation of results:

not irritating

Remarks:

Migrated information Criteria used for interpretation of results: EU

Conclusions:

The highest total mean score was 4.0 occurring at the one hour observation; accordingly under the criteria of Kay and Calandra (1962) ST888YK was classified as "minimally irritating" to the eye.
The test material is not considered to be classified as irritating to eyes according to Regulation (EC) No 1272/2008.

Executive summary:

A study was performed to assess the eye irritation potential of ST888YK to the rabbit. The method followed was that described in:

EEC Methods for the determination of toxicity, Annex to Directive 92/69/EEC (Official Journal No. L383A, 29.12.92), Part B, Method B.5. Acute toxicity (eye irritation).

OECD Guideline for the Testing of Chemicals No. 405, "Acute Eye Irritation/Corrosion", Adopted 24 February 1987.

EPA Health Effects Test Guidelines OPPTS 870.2400 Acute Eye Irritation EPA 712-C-98-195. August 1998.

Three rabbits were each administered a single ocular dose of a volume of 100 mg of the test substance. Reactions to treatment were assessed 1, 24, 48 and 72 hours and seven days after instillation.

Injection of the conjunctival blood vessels with or without very-slight or slight discharge was apparent during the first twenty-four hours after instillation. The injection was apparent in two animals at the 48-hour assessment and in one animal 24 hours later. No other ocular reaction was apparent in any animal at any time.

Instillation of the test substance gave rise to a moderate initial pain response in one animal; no pain response was evident in the other two animals.

The means of scores for the ocular reactions at approximately 24, 48 and 72 hours after administration, calculated separately for each animal, are summarised below:

Animal number	Corneal opacity	Iridial lesions	Conjunctival
			Redness	Chemosis
3984	0.0	0.0	1.0	0.0
4117	0.0	0.0	0.3	0.0
4118	0.0	0.0	0.7	0.0
EC R36 trigger values*	≥ 2 < 3	≥ 1 < 2	≥ 2.5	≥ 2
EC R41 trogger values*	≥ 3	= 2

* Classification triggered if any value is attained by two or more animals.

The total mean scores (according to the system of Kay and Calandra (1962)) are summarised below:

	Time after instillation of ST888YK
Area of eye	1 hour	24 hours	48 hours	72 hours	7 days
Cornea	0.0	0.0	0.0	0.0	0.0
Iritis	0.0	0.0	0.0	0.0	0.0
Conjunctiva	4.0	3.3	1.3	0.7	0.0
Total mean score	4.0	3.3	1.3	0.7	0.0

The highest total mean score was 4.0 occurring at the one hour observation; accordingly under the criteria of Kay and Calandra (1962) ST888YK was classified as "minimally irritating" to the eye.

Endpoint conclusion

Endpoint conclusion:

no adverse effect observed (not irritating)

Respiratory irritation

Endpoint conclusion

Endpoint conclusion:

no study available

Additional information

Skin Irritation

A study was performed to assess the skin irritation potential of ST888YK to the rabbit. The method followed was that described in:

EEC Methods for the determination of toxicity, Annex to Directive 92/69/EEC (Official Journal No. L383A, 29.12.92), Part B, Method B.4. Acute toxicity (Skin Irritation).

OECD Guideline for Testing of Chemicals No. 404 "Acute Dermal Irritation/Corrosion". Adopted 17 July 1992.

EPA Health Effects Test Guidelines OPPTS 870.2500 Acute Dermal Irritation EPA 712-C-98196. August 1998.

Three rabbits received a single four hour, semi-occlusive, dermal administration of approximately 0.5 g of the test substance as supplied and were observed for four days.

No dermal irritation was observed in any animal throughout the duration of the study.

The means of scores for these reactions at approximately 24, 48 and 72 hours after administration, calculated separately for each animal, are summarised below:

Means of scores at approximately 24, 48 and 72 hours
Animal number	Erythema	Oedema
3945	0.0	0.0
3960	0.0	0.0
3962	0.0	0.0
EC trigger values*	≥ 2	≥ 2

*Classification is triggered if means of scores for either effect are ≥ 2 for two or three animals (or if effects persist to Day 14 in at least two animals).

The Primary Irritation Index (PII) was calculated to be 0.0 and ST888YK was classified as "non irritant" in accordance with the criteria of ECETOC.

The test material is not considered to be classified as irritating to skin according to Regulation (EC) No 1272/2008.

Eye Irritation

A study was performed to assess the eye irritation potential of ST888YK to the rabbit. The method followed was that described in:

EEC Methods for the determination of toxicity, Annex to Directive 92/69/EEC (Official Journal No. L383A, 29.12.92), Part B, Method B.5. Acute toxicity (eye irritation).

OECD Guideline for the Testing of Chemicals No. 405, "Acute Eye Irritation/Corrosion", Adopted 24 February 1987.

EPA Health Effects Test Guidelines OPPTS 870.2400 Acute Eye Irritation EPA 712-C-98-195. August 1998.

Three rabbits were each administered a single ocular dose of a volume of 100 mg of the test substance. Reactions to treatment were assessed 1, 24, 48 and 72 hours and seven days after instillation.

Injection of the conjunctival blood vessels with or without very-slight or slight discharge was apparent during the first twenty-four hours after instillation. The injection was apparent in two animals at the 48-hour assessment and in one animal 24 hours later. No other ocular reaction was apparent in any animal at any time.

Instillation of the test substance gave rise to a moderate initial pain response in one animal; no pain response was evident in the other two animals.

The means of scores for the ocular reactions at approximately 24, 48 and 72 hours after administration, calculated separately for each animal, are summarised below:

Animal number	Corneal opacity	Iridial lesions	Conjunctival
			Redness	Chemosis
3984	0.0	0.0	1.0	0.0
4117	0.0	0.0	0.3	0.0
4118	0.0	0.0	0.7	0.0
EC R36 trigger values*	≥ 2 < 3	≥ 1 < 2	≥ 2.5	≥ 2
EC R41 trogger values*	≥ 3	= 2

* Classification triggered if any value is attained by two or more animals.

The total mean scores (according to the system of Kay and Calandra (1962)) are summarised below:

	Time after instillation of ST888YK
Area of eye	1 hour	24 hours	48 hours	72 hours	7 days
Cornea	0.0	0.0	0.0	0.0	0.0
Iritis	0.0	0.0	0.0	0.0	0.0
Conjunctiva	4.0	3.3	1.3	0.7	0.0
Total mean score	4.0	3.3	1.3	0.7	0.0

The highest total mean score was 4.0 occurring at the one hour observation; accordingly under the criteria of Kay and Calandra (1962) ST888YK was classified as "minimally irritating" to the eye.

Justification for selection of skin irritation / corrosion endpoint:
The Primary Irritation Index (PII) was calculated to be 0.0 and ST888YK was classified as "non irritant" in accordance with the criteria of ECETOC.
The test material is not considered to be classified as irritating to skin according to Regulation (EC) No 1272/2008.

Justification for selection of eye irritation endpoint:
The highest total mean score was 4.0 occurring at the one hour observation; accordingly under the criteria of Kay and Calandra (1962) ST888YK was classified as "minimally irritating" to the eye.
The test material is not considered to be classified as irritating to eyes according to Regulation (EC) No 1272/2008.

Justification for classification or non-classification

Based on the results of the above studies, the test material can be considered not to be classified for irritation in both the skin and eye.